The search for kinase inhibitors has proven to be a fruitful area for the development of useful pharmaceutically active substances. Kinases, which are alternatively known as phosphotransferases, are enzymes that transfer phosphate groups from high energy donor molecules (for example ATP) to specific target molecules (typically called substrates) in a process termed phosphorylation. One of the largest groups of kinases are the protein kinases which act on and modify the activity of specific proteins.
As a result of the potential of kinase inhibitors to act as pharmaceutically active compounds a significant amount of research has been carried out to discover compounds that display appropriate activity against these targets. In the cancer area two kinases that have attracted attention as potential targets for therapeutic compounds include mTOR and PI3. An example of research in this area is that disclosed in PCT/SG2008/000379 which discloses a number of compounds having kinase activity against both mTOR and PI3.
Compounds that inhibit both mTOR and PI3 kinases simultaneously may be expected to provide powerful anti-proliferative, anti-angiogenic and antitumor activity since these compounds act at multiple points in the PI3K/Akt/mTOR pathway. A number of inhibitors of this type are now being investigated in a clinical setting for the first time (e.g. BEZ235, XL765, GDC0941, PX866, SF1126).
In the search for suitable drug candidates a number of factors are taken into consideration in the final determination of whether a compound is a suitable drug candidate or not. Accordingly in making an assessment of a potential compound for further development a number of factors are taken into consideration in addition to the primary inhibitory activity of the compound per se. In making this assessment the skilled medicinal chemist looks at the “drug like properties” of the molecule and includes an assessment of factors such as its activity against the target of interest, the solubility of the compounds of interest (if they are not soluble they typically make poor drug candidates), the metabolic stability of the compound in vitro and in vivo, and the potential side effects that could be caused by the compound on the body amongst others. The present applicants have identified a compound with significantly improved drug like properties in comparison with other compounds in the area.